From the Division of Hematology and Oncology, University of North Carolina – Chapel Hill, Chapel Hill, NC (Dr. Reeves), and the Division of Cellular Therapy and Hematological Malignancies, Duke Cancer Institute, Durham, NC (Dr. Tuchman).
Abstract
Objective: To review the management considerations in patients with relapsed and refractory multiple myeloma (RRMM).
Methods: Review of the literature.
Results: RRMM is a heterogeneous disease and numerous treatment regimens have been studied. Despite improvement in progression-free and overall survival in newly diagnosed multiple myeloma with current therapies, myeloma remains incurable and repeated relapses are inevitable. Relapses are often characterized by diminished response to chemotherapy (refractoriness) and duration of response.
Conclusion: Management of RRMM should be individualized using both patient- and disease-related factors, given substantial heterogeneity in both. Further research regarding the optimal timing, regimen, and duration of treatment is warranted.
Although advancements in treating multiple myeloma (MM) have resulted in improved median survival from approximately 2 years in the 1990s to more recent estimates of over 6 years, the disease remains incurable [1–3]. Its overall course is generally defined by a series of increasingly short remissions and treatment-refractory relapses until eventual death due to MM occurs. Objective criteria for defining both relapsed and refractory MM have been published [4]. Briefly, relapsed myeloma is that which has been previously treated with some form of systemic therapy and which has recurred. That recurrence can be clinical (ie, the development of new or worsening signs or symptoms of active MM) and/or biochemical (ie, rising monoclonal MM proteins in the serum or urine). Refractory MM on the other hand refers to MM that is resistant to particular drugs, defined as MM that is nonresponsive to primary or salvage therapy, or MM that progresses within 60 days of the last therapy [4]. At any juncture during the course of relapsed MM, patients will have disease that is either sensitive or refractory to specific myeloma drugs. In this article, we discuss management of these often concurrent entities together as relapsed and refractory multiple myeloma (RRMM).
There are numerous treatment options for patients with RRMM—3 new drugs were approved in November 2015 alone. The abundance of available drugs leaves treating clinicians with a daunting task of sequencing therapies among several choices. The durability of response to treatment typically lessens with each disease relapse, such that the clinician needs to think of sequencing not just second-line therapy, but third- and fourth-line as well, further complicating the decision. In this review, we aim to help clinicians individualize treatment plans for patients with RRMM.
Case Studies
Patient A
A 62-year-old man with IgG-kappa MM was diagnosed 4 years ago during evaluation of a pathologic humeral fracture. The disease was prognostically standard risk, with revised International Staging System (RISS) stage I disease (beta-2 microglobulin 3.4 mcg/mL, albumin 4.1 g/dL, normal cytogenetics with 46,XY in 20 cells analyzed, and myeloma fluorescent in situ hybridization [FISH] panel showing t(11;14) but no del17p, t(14;16), t(14;20), or t(4;14)) [5], and normal blood counts, organ function, and lactate dehydrogenase (LDH) at diagnosis. He was treated with 5 cycles of standard lenalidomide, bortezomib, and dexamethasone followed by high-dose melphalan with autologous stem cell transplantation (ASCT) and then lenalidomide continuous maintenance. He achieved a stringent complete response (ie, complete disappearance of myeloma-derived monoclonal proteins in the serum and urine, a normal serum free light chain ratio, and undetectable monoclonal plasma cells on a bone marrow aspirate and biopsy) [4]. His MM was monitored every 2 to 3 months for disease progression and medication toxicity. At month 38, a monoclonal protein spike (M-spike) on serum protein electrophoresis (SPEP) remained undetectable, but serum kappa free light chain levels increased from 1.98 mg/dL to 8 mg/dL with stable lambda serum free light chains and a ratio that rose to 16, consistent with low-level biochemical recurrence. He had no evidence of end-organ damage and therefore was maintained on lenalidomide maintenance for the time being. Over the next 12 months, his kappa serum free light chain level continued to slowly rise, reaching 24 mg/dL, while the ratio rose to 50. There was still no detectable M-spike. He developed mild anemia during this time, with his hemoglobin dropping from a prior value of approximately 11 g/dL to 9.8 g/dL, though kidney function remained normal. A repeat bone marrow aspirate and biopsy revealed 20% kappa-restricted plasma cells.
